Pyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles

ABSTRACT

Novel pyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles, intermediates and processes for the preparation thereof, and methods of relieving memory dysfunction and treating depression utilizing the 1,2-benzisoxazoles and -benzisothiazoles and intermediates, or compositions thereof are disclosed.

This is a division of application Ser. No. 08/806,981, filed Feb. 26,1997, now U.S. Pat. No. 5,728,717, which is a divisional of Ser. No.08/637,091, filed May 2, 1996, now U.S. Pat. No. 5,668,154, which is acontinuation in part of Ser. No. 08/466,021, filed Jun. 6, 1995 nowabandoned, which are herein incorporated by reference.

The present invention relates to 1,2-benzisoxazoles and--benzisothiazoles. More particularly, the present invention relates topyridiniminyl-1,2-benzisoxazoles and --benzisothiazoles of formula 1##STR1## wherein R₁ is hydrogen, loweralkyl, loweralkenyl, loweralkynyl,lowercycloalkyl, --C(═O)O-loweralkyl, 1,3-dioxolane, phenyl, cinnamyl,phenyl substituted by loweralkyl, loweralkoxy, halogen, hydroxyl, nitroor trifluoromethyl; Q is hydrogen, halogen, loweralkyl or nitro; X isoxygen or sulfur; Z is hydrogen, loweralkyl, loweralkoxy, hydroxyl,halogen, nitro, or trifluoromethyl; n is 1 to 12; the geometric isomers,the optical isomers, or the pharmaceutically acceptable salts thereof,useful in relieving memory dysfunction and thus indicated in thetreatment of Alzheimer's disease, as well as in the treatment ofdepression.

Subgeneric to the compounds of formula 1 are those wherein X is oxygenand R₁ is hydrogen or loweralkyl; and those wherein X is oxygen and R₁is phenyl or phenyl substituted by loweralkyl, loweralkoxy, halogen,hydroxyl, nitro, or trifluoromethyl.

The present invention further relates topyridinylamino-1,2-benzisoxazoles and -benzisothiazoles of formula 2##STR2## wherein Q is hydrogen, halogen, loweralkyl or nitro; X isoxygen or sulfur; Z is hydrogen, loweralkyl, loweralkoxy, hydroxyl,halogen, nitro, or trifluoromethyl; the optical isomers, orpharmaceutically acceptable salts thereof, useful as intermediates forthe preparation of the pyridiniminyl-1,2-benzisoxazoles and-benzisothiazoles of formula 1 and also for the relief of memorydysfunction and treatment of depression.

Unless otherwise noted, the following terms have the given definitions.As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no saturation and having 1 to 8 carbon atoms. Examples ofalkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-hexyl,3-hexyl, 4-heptyl, 2-octyl and the like. The term "alkoxy" refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen having its free valence bond from the ether oxygen.Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butoxy,1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy and the like. The term"alkenyl" refers to a straight or branched chain hydrocarbon radicalcontaining unsaturation in the form of a single carbon to carbon doublebond and having from 3 to 7 carbon atoms such as propenyl, 2-butenyl,3-ethyl-2-pentenyl, and the like; the term "alkynyl" refers to astraight or branched chain hydrocarbon radical containing unsaturationin the form of a single carbon to carbon triple bond and having from 3to 7 carbon atoms such as 2-propynyl, 2-butynyl, 1-methyl-2-butynyl,4-methyl-2-pentynyl, 4,4-dimethyl-2-butynyl and the like; the term"cycloalkyl" refers to a saturated hydrocarbon group possessing at leastone carbocyclic ring, the ring containing from 3 to 10 carbon atoms suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloctyl,1-adamantyl and the like. The term "alkanol" refers to a compound formedby a combination of an alkyl group and hydroxy radical. Examples ofalkanols are methanol, ethanol, 1- and 2-propanol, 2,2-dimethylethanol,hexanol, octanol and the like. The terms "halogen", "Hal" or "halo"refers to a member of the family fluorine, chlorine, bromine, or iodine.The term "lower" as applied to any of the aforementioned groups refersto a group having a carbon skeleton containing up to and including 6carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted. In addition, the patentapplication entitled "PYRIDINIMINYL-1,2-BENZISOXAZOLES AND-BENZISOTHIAZOLES", U.S. Ser. No. 08/466,021, filed Jun. 6, 1995, isincorporated herein by reference.

The novel pyridiniminyl-1,2-benzisoxazoles can be prepared followingsteps A, A' and B as set forth in the Reaction Scheme.The-benzisothiazoles of the present invention can be prepared followingsteps A and B as set forth in the Reaction Scheme.

As described in the Reaction Scheme, steps A and B, to prepare apyridiniminyl-1,2-benzisoxazole of formula 1, wherein X is oxygen, forexample, a pyridiniminyl-1,2-benzisoxazole 1, an aminobenzisoxazole 3 iscondensed with a halopyridine of formula 5 ##STR3## wherein Hal ischloro or bromo and Q is as above to yield apyridinylamino-1,2-benzisoxazole 2 wherein X, Q, and Z are as above,which, in turn, is alkylated with an alkyl halide of formula 6 ##STR4##wherein Hal is chloro or bromo and R₁ and n are as above to yield anultimate pyridiniminylbenzisoxazole 1 wherein R₁, Q, X, Z, and n are asabove.

The condensation of amine 3 with halopyridine 5 is generally performedin a polar aprotic solvent, for example, N-methylpyrrolidinone,dimethylacetamide, dimethylformamide, hexamethylphosphoramide, ordimethylsulfoxide. While the condensation temperature is not narrowlycritical, elevated temperatures in the range of about 100° to about 150°C. may be employed to facilitate the reaction, depending on the reactionsolvents. A condensation temperature of about 130° C. is preferred.

The alkylation is conveniently carried out in an inert solvent such asacetonitrile at the reflux temperature of the reaction medium. Thealkylation may be performed at reduced temperatures, for example, withinthe range of from about ambient temperature to approaching about thereflux temperature of the medium.

Alternatively, the alkylation may be achieved in an inert solvent suchas an protic dipolar solvent (dimethylacetamide, dimethylsulfoxide,hexamethylphosphoramide and the like) in the presence of a base such as,for example, an alkali metal hydride, namely lithium, sodium orpotassium hydride, sodium hydride being preferred. The alkylationtemperature may vary from about ambient to about 80° C. An alkylationtemperature of about 60° C. is preferred.

The starting 3-amino-1,2-benzisoxazole 3, for example, anaminobenzisoxazole 3, wherein X is oxygen and Z is as above iscommercially available or preparable by the process described in G. M.Shutske and K. J. Kapples, Journal of Heterocyclic Chemistry, 26, 1293(1989). In addition, the starting 3-amino-1,2-benzisothiazoles arereadily prepared by one of ordinary skill in the art, for example,following the procedures as disclosed by Rahman and Scrowston, J. Chem.Soc. Perkin Trans. I, 2973 (1983) and 385 (1984).

As described in the Reaction Scheme, steps A' and B, the intermediate3-pyridinylamino-1,2-benzisoxazole 2, for example, a pyridinylaminobenzisoxazole 2 wherein X is oxygen and Q and Z are as above, in thealternative, may be prepared by treating a 2-fluoro or2-nitro-N-4-pyridinylbenzamide 7 with thionyl chloride followed bytreating the imidoylchloride, so obtained, generally withoutpurification, with O-trimethylsilylhydroxyl amine, to afford anamidoxime, and treating the amidoxime, also without purification, with abase to yield a pyridinyl-1,2-benzisoxazole 2. Specifically,2,5-difluoro-N-pyridinylbenzamide 7, wherein Q is hydrogen and Z is5-fluoro is treated with thionyl chloride in the presence or absence ofa solvent (1,1-dichloroethane) at the reflux temperature of the reactionmedium to provide 2,5-difluorophenyl-N-(1H)-pyridinimidoyl chloridewhich, in turn, is treated with O-trimethylsilylhydroxyl amine in anethereal solvent such as tetrahydrofuran at ambient temperature to give2,5-difluoro-4-(pyridinylamino)methanone oxime and the latter with analkali metal alkoxide such as potassium t-butoxide in an ethereal ordipolar aprotic solvent such as tetrahydrofuran or dimethylformamide,respectively, at an elevated temperature to yield 5-fluoro-3-4-(pyridinyl)amino!-1,2-benzisoxazole.

One of ordinary skill in the art would readily recognize that thecorresponding 1,2-benzisothiazoles of the present invention are preparedin a manner analogous to the procedure described in the Reaction Scheme,steps A and B as set forth above for preparing the 1,2-benzisoxazoles 2and 3.

The pyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles and relatedcompounds of the present invention are useful as agents for the reliefof memory dysfunction, particularly dysfunctions associated withdecreased cholinergic activity such as those found in Alzheimer'sdisease. Relief of memory dysfunction activity is demonstrated in the invitro inhibition of acetylcholinesterase assay, an assay for thedetermination of the ability of a drug to inhibit the inactivation ofacetylcholine, a neurotransmitter implicated in the etiology of memorydysfunction and Alzheimer's dementia. In this assay, a modification of atest described by G. L. Ellman, et al., Biochemical Pharmacology, 7, 88(1961), the following reagents are prepared and employed:

1. 0.05M Phosphate Buffer (pH 7.2)

A solution of monobasic sodium phosphate monohydrate (6.85 g) indistilled water (100 mL) is added to a solution of dibasic sodiumphosphate heptahydrate (13.4 g) and distilled water (100 mL) until a pHof 7.2 was attained. The solution was diluted 1 to 10 with distilledwater.

2. Substrate in Buffer

The 0.05M Phosphate Buffer (pH 7.2) was added to acetylthiocholine (198mg) to a total volume of 100 mL, i.e., a quantity sufficient (gs) to 100mL.

3. 5,5-Dithiobisnitrobenzoic acid in Buffer

The 0.05M Phosphate Buffer (pH 7.2) was added to5.5-dithiobisnitrobenzoic acid to a total volume of 100 mL. i.e., aquantity sufficient (gs) to 100 mL.

4. Stock Solution of Drug

A 2 millimolar stock solution of the test drug is prepared in a quantitysufficient of either acetic acid or dimethyl sulfoxide to volume with5,5-Dithiobisnitrobenzene Acid in Buffer. Stock Solution of Drug isserially diluted (1:10) so that the final cuvette concentration is 10⁻⁴molar.

Male Wistar rats are decapitated, brains rapidly removed, corporastriata dissected free, weighted and homogenized in 19 volumes(approximately 7 mg protein/mL) of 0.05M phosphate Buffer (pH 7.2) usinga Potter-Elvehjem homogenizer. A 25 μl aliquot of this suspension isadded to 1 mL of the vehicle or various concentrations of the test drugand preincubated for 10 minutes at 37° C. Enzyme activity is measuredwith a Beckman DU-50 spectrophotometer with the following software andinstrument settings:

1. Kinetics Soft-Pac™ Module #598273;

2. Program #6 Kindata;

3. Source--Vis;

4. Wavelength--412 nm;

5. Sipper--none;

6. Cuvettes--2 mL cuvettes using auto 6-sampler;

7. Blank--1 for each substrate concentration;

8. Interval time--15 seconds (15 or 30 seconds for kinetics);

9. Total time--5 minutes (5 to 10 minutes for kinetics);

10. Plot--yes;

11. Span--autoscale;

12. Slope--increasing;

13. Results--yes (gives slope); and

14. Factor--1.

Reagents are added to the blank and sample cuvettes as follows:

    ______________________________________                                        1.   Blank   0.8 mL 5.5-Dithiobisnitrobenzoic Acid                                         0.8 mL Substrate in Buffer                                       2.   Control 0.8 mL 5.5-Dithiobisnitrobenzoic Acid/Enzyme                                  0.8 mL Substrate in Buffer                                       3.   Drug    0.8 mL 5.5-Dithiobisnitrobenzoic Acid/Drug/Enzyme                             0.8 mL Substrate in Buffer                                       ______________________________________                                    

Blank values are determined for each run to control for non-enzymatichydrolysis of substrate and these values are automatically subtracted bythe Kindata program available on kinetics soft-pac module. This programalso calculates the rate of absorbance change for each cuvette.

For IC₅₀ Determinations

Substrate concentration is 10 millimolar diluted 1:2 in assay yieldingfinal concentration of 5 millimolar. 5,5-Dithiobisnitrobenzoic acidconcentration is 0.5 millimolar yielding 0.25 millimolar finalconcentration. ##EQU1##

IC₅₀ values are calculated from log-probit analysis

                  TABLE I                                                         ______________________________________                                                               Inhibition of                                                                 Acetylcholinesterase                                   Compound               Activity IC.sub.50 (μM)                             ______________________________________                                        3- 1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-                                                        0.28                                                   benzisoxazole                                                                 3- 1-phenylpropyl-N-4(1H)-pyridiniminyl!-1,2-                                                        0.65                                                   benzisoxazole                                                                 6-Methoxy-3- 1-phenylmethyl-N-4(1H)-                                                                 0.09                                                   pyridiniminyl!-1,2-benzisoxazole                                              3- 1-(4-fluorophenyl)methyl-N-4(1H)-                                                                 0.44                                                   pyridiniminyl!-1,2-benzisoxazole                                              tacrine                0.32                                                   ______________________________________                                    

Relief of memory dysfunction is achieved when the presentpyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles and relatedcompounds are administered to a subject requiring such treatment as aneffective oral, parenteral or intravenous dose of from 0.10 to 50 mg/kgof body weight per day. A particularly effective amount is about 10mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The pyridiniminyl-1,2-benzisoxazoles and -benzisothiazoles of thepresent invention are also useful as agents for treating depression.Depression treatment is demonstrated in the in vitro inhibition ofmonoamine oxidase assay, an assay for the determination of the abilityof a drug to inhibit the enzyme monoamine oxidase. In this assay, amodification of an assay described by M. V. Kindt, et al., Europ. J.Pharmacol. 146: 313-318 1988.

The following reagents are prepared:

1. Phosphate buffer (0.5M), pH 7.4;

134.4 g dibasic sodium phosphate heptahydrate q.s. to 1 liter indistilled water (A)

17.3 g monobasic sodium phosphate q.s. to 250 mL in distilled water (B)

Adjust pH of A to 7.4 by slowly adding B (volumes as needed)

Dilute 1:10 in distilled water (0.05M phosphate buffer, pH 7.4)

2. 0.25M Sucrose (phosphate buffered):

21.4 g sucrose, q.s. to 250 mL with 0.05M phosphate buffer

3. Substrate for monoamine oxidase-A:

a. serotonin creatine sulphate (5-hydroxytryptamine) is obtained fromSigma Chemical Company. A 5 mM stock solution is made up in 0.01N-hydrochloride. The solution is used to dilute the specific activity ofthe ³ H!-hydroxytryptamine.

b. ³ H!-5-Hydroxytryptamine binoxalate (20-30 Ci/mmol) is obtained fromNew England Nuclear.

c. Add 12 μl of ³ H!-5-hydroxytryptamine to 2 mL of the 5 mN5-hydroxytryptamine solution. (Final amine concentration in the assay is200 μM: see below.)

4. Substrate for monoamine oxidase-B

a. -phenethylamine is obtained from Sigma Chemical Company. A 5 mM stocksolution is made up in 0.01 N-hydrochloride. The solution is used todilute the specific activity of the ¹⁴ C!- --phenethylamine.

b. -- ethyl-1-¹⁴ C!-phenethylamine hydrochloride (40-50 mCi/mmol) isobtained from New England Nuclear.

c. Add 12 μl of ¹⁴ C!- --phenethylamine to 2 mL of the 5mM--phenethylamine solution. (Final amine concentration in the assay is200 μM: see below.)

5. Equal amounts of monoamine oxidase-A (5-hydroxytryptamine) andmonoamine oxidase-B (-phenethylamine) substrates are combined forsimultaneously testing both monoamine oxidase types, i.e., mixed stocksolution of 2.5 mN 5-hydroxytryptamine and 2.5 mM -phenethylamine, 40 μlof this mixed solution gives a 200 μM final concentration of each aminein the assay. When testing only one monoamine oxidase type, theindividual 5 mM stock solutions must be diluted 1:1 with distilled waterprior to adding 40 μl to the incubation mixture; i.e., same 200 μM finalamine concentration.

6. Stock solutions of test drugs are made up in appropriate vehicles andserially diluted to give final concentrations ranging from 10⁻⁷ to 10⁻³molar in the assay. Lower concentrations can be made for more potentdrugs.

Tissue Preparation

Male Wistar rats weighing 150-250 grams were sacrificed and the brainsrapidly removed. Whole brain minus cerebellum was homogenized in 30volumes of ice-cold phosphate-buffered 0.25M sucrose, using aPotter-Elvejhem homogenizer. The homogenate was centrifuged at 1000 gfor 10 minutes and the supernatant (S₁) decanted and recentrifuged at18,000 g for 20 minutes. The resulting pellet (P₂) was resuspended infresh 0.25M sucrose and serves as the tissue source for mitochondrialmonoamine oxidase.

C. Assay

10 μl 0.5M phosphate buffer, pH 7.4

50 μl water or appropriate drug concentration

400 μl Tissue suspension

Tubes are preincubated for 15 minutes at 37° C. and the assay is startedby adding 40 μl of combined substrate ( ³ H!-5-hydroxytryptamine and ¹⁴C!- -phenethylamine) at 15 second intervals. The tubes are incubated for30 minutes at 37° C. and the reaction stopped by the addition of 0.3 mL2N-hydrochloric acid. Tissue blank values are determined by adding theacid before the radioactive substrate. The oxidative products of thereaction are extracted with ethyl acetate/toluene (1:1). Add 5 mL ofthis mixture to the tubes, vortex for 15 seconds to extract thedeaminated metabolites into the organic phase and allow to separate fromthe aqueous phase. Place tubes in acetone/dry ice bath to freeze theaqueous layer. When this layer is frozen, pour off the top organic layerinto a scintillation vial. Add 10 mL Liquiscint and count the samplesusing window settings for ¹⁴ C in one channel and ³ H in the secondchannel. IC₅₀ values are determined by log-probit analysis.

Results

                  TABLE II                                                        ______________________________________                                                       Monoamine           Monoamine                                  Compound       Oxidase A IC50 (μM)                                                                            Oxidase B                                  ______________________________________                                        6-Chloro-3- 1-propyl-N-                                                                       1.65               27.2                                       4(1H)pyridiniminyl-1,2-                                                       benzisoxazole                                                                 3- 1-phenylmethyl-N-4(1H)-                                                                   9.0                 33.7                                       pyridiniminyl!-1,2-                                                           benzisoxazole                                                                 3- 1-(2-phenylethyl)-N-4(1H)-                                                                3.0                 15.9                                       pyridiniminyl!-1,2-                                                           benzisoxazole                                                                 6-Methoxy-3- 1-phenyl-                                                                       3.0                 25.2                                       methyl-N-4(1H)-pyridini-                                                      minyl!-1,2-benzisoxazole                                                      brofaromine     0.18               23.4                                       ______________________________________                                    

Depression treatment is achieved when the presentpyridiniminyl-1,2-benzisoxazoles or -benzisothiazoles and relatedcompounds are administered to a subject requiring such treatment as aneffective oral, parenteral or intravenous dose of from 0.10 to 50 mg/kgof body weight per day. A particularly effective amount is about 10mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

Acetylcholinesterase inhibitors and monoamine oxidase inhibitors areknown in the art as being useful as relievers of memory dysfunction andantidepressants, respectively. (See V. Kumar in Alzheimer's Disease:Therapeutic Strategies, E. Giacobini and R. Becker Eds.; Birkhauser,Boston 1994 for memory dysfunction utility and K. F. Tipton inBiochemical and Pharmacological Aspects of Depression, K. F. Tipton andU. B. H. Youdin, Eds., Taylor and Francis, London 1989 forantidepressant utility. It is understood by one of ordinary skill in theart that humans, mice, rats and the like are included within the scopeof the term "mammal".

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tables, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tables. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompounds, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0 -300 mg of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl, salicylate,or orange flavoring may be added. When the dosage unit is a capsule itmay contain, in addition to materials of the above type, a liquidcarrier such as fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight hereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mg of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerin, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteralpreparations can be enclosed in ampules, disposable syringes or multiplevials made of glass or plastic.

Compounds of the invention include:

a. 6-methyl-3- 1-propyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

b. 5-hydroxy-3- 1-methyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

c. 3- 1-ethyl-N-4(1H)pyridiniminyl!-5-trifluoromethyl-1,2-benzisoxazole;

d. 3- 1-(2-propenyl)-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

e. 3- 1-(2-propynyl)-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

f. 3- 1-cyclohexyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

g. 3- 1-(4-hydroxyphenylmethyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

h. 3- 1-propyl-N-4(1H)pyridiniminyl!-1,2-benzisothiazole;

i. 3- 1-propyl-N- 2-chloro-4(1H)pyridiniminyl!-1,2-benzisoxazole;

j. 3- 1-propyl-N- 2-methyl-4(1H)pyridiniminyl!-1,2-benzisoxazole;

k. 3- 1-propyl-N- 2-nitro-4(1H)pyridiniminyl!-1,2-benzisoxazole;

l. 3- 1-decyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole;

m. 5-methyl-3-(4-pyridinylamino)-1,2-benzisoxazole;

n. 6-hydroxy-3-(4-pyridinylamino)-1,2-benzisoxazole;

o. 7-nitro-3-(4-pyridinylamino)-1,2-benzisoxazole;

p. 3-(4-pyridinylamino-3-trifluoromethyl)-1,2-benzisoxazole;

q. 3-(2-chloro-4-pyridinylamino)-1,2-benzisoxazole;

r. 3-(2-methyl-4-pyridinylamino)-1,2-benzisoxazole;

s. 3-(2-nitro-4-pyridinylamino)-1,2-benzisoxazole; and

t. 3-(4-pyridinylamino)-1,2-benzisothiazole.

The following examples present typical syntheses as described in theReaction Scheme. The reagents and starting materials are commerciallyavailable or are readily prepared by one of ordinary skill in the art.These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following terms have the indicated meanings: "kg" refers tokilograms; "g" refers to grams; "mg" refers to milligrams; "μg" refersto micrograms; "ppm" refers to parts per million; "mmol" refers tomillimoles; "mL" refers to milliliters; "cm" refers to centimeters; "L"refers to liters; "° C." refers to degrees Celsius; "mm Hg" refers tomillimeters of mercury; "rpm" refers to revolutions per minute; "R_(f) "refers to retention factor; "bp" refers to boiling point; "mp" refers tomelting point; "dec" refers to decomposition; " α!^(D) ₂₀ " refers tospecific rotation of the D line of sodium at 20° C. obtained in a 1decimeter cell; "c" refers to concentration in g/mL; "TFA" refers totrifluoroacetic acid; "THF" refers to tetrahydrofuran, "DMF" refers todimethylformamide, "M" refers to molar; "mM" refers to millimolar; "μM"refers to micromolar; "nM" refers to nanomolar; "μL" refers tomicroliters; "HPLC" refers to high performance liquid chromatography;"eq" refers to equivalents; "hr." refers to hours; "N" refers to normal;and "μCi" refers to microcuries.

EXAMPLE ONE ##STR5##6-Chloro-3-!1-propyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazolehydrochloride

To a suspension of pentane washed sodium hydride (380 mg) indimethylformrnamide (5 mL) was added 1-bromopropane (0.862 mL) followedby 6-chloro-3-(4-pyridyl)amino-1,2-benzisoxazole (2.33 g) indimethylformamide (10 mL) dropwise. After stirring for 1.5 hr., anadditional 0.3 mL of 1-bromopropane was added, and the reaction mixturewas heated to 60° C. for one-half hr. The reaction mixture was cooledand distributed between diethyl ether and water. The precipitate wascollected and washed with water and diethyl ether to yield 1.21 g offree base product. The free base was taken up in methanol/etherealhydrogen chloride, and the solution was concentrated. The residue wastriturated with diethyl ether and then recrystallized frommethanol/diethyl ether to yield 992 mg (32%) of product from two crops,mp 278° C. (d), after drying under high vacuum, phosphorous pentoxide,and refluxing xylenes.

Analysis:

    ______________________________________                                        Calculated for C.sub.15 H.sub.14 N.sub.3 OCl--HCl                                               55.57% C 4.66% H  12.96% N                                  Found             55.39% C 4.55% H  12.97% N                                  ______________________________________                                    

EXAMPLE TWO ##STR6## 3-1-(4,4-Dimethyl)pentyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.2 g) and1-bromo-4-dimethyl-pentane (3.1 g) in acetonitrile (25 mL) was heatedunder reflux for 24 hr. The reaction mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo, to afford 0.60 g, (27%) ofproduct. Two recrystallizations from isopropanol yielded theanalytically pure sample, mp236-237° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.24 BrN.sub.3 O                                                 58.46% C  6.21% H   10.77% N                                   Found          58.18% C  5.91% H   10.70% N                                   ______________________________________                                    

EXAMPLE THREE ##STR7## 3-1-Phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.84 g) andbenzyl bromide (0.68 g) in acetonitrile (20 μL) was heated under refluxfor 1.5 hr. The reaction mixture was allowed to cool to roomtemperature., and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo, to afford 1.4 g (92%) ofproduct, mp 285-287° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.16 BrN.sub.3 O                                                 59.70% C  4.22% H   10.99% N                                   Found          59.64% C  4.34% H   11.15% N                                   ______________________________________                                    

EXAMPLE FOUR ##STR8## 3-1-(2-Phenylethyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) andphenethyl bromide (0.87 g) in acetonitrile (19 mL) was heated underreflux for 10 hr. The reaction mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.0 g (54%) ofproduct mp 259-261° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O                                                 60.62% C  4.58% H   10.60% N                                   Found          60.41% C  4.61% H   10.61% N                                   ______________________________________                                    

EXAMPLE FIVE ##STR9## 3-1-(3-Phenylpropyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.07 g) and3-phenylpropyl bromide (1.51 g) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo, to afford 1.27 g (61 %) of product, mp226-227° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.21 H.sub.20 BrN.sub.3 O                                                 61.47% C  4.91% H   10.24% N                                   Found          61.37% C  5.11% H   10.15% N                                   ______________________________________                                    

EXAMPLE SIX ##STR10## 3-1-(4-Phenylbutyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and1-bromo-4-phenylbutane (1.0 g) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.30 g (65%) of product, mp207-208° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.22 H.sub.22 BrN.sub.3 O                                                 62.27% C  5.23% H   9.90% N                                    Found          62.26% C  5.18% H   9.90% N                                    ______________________________________                                    

EXAMPLE SEVEN ##STR11## 3-1-(5-Phenylpentyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and1-bromo-5-phenylpentane (1.13 g) in acetonitrile (25 mL) was heatedunder reflux for 24 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 0.85 g (41%) ofproduct, mp 213-214° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.23 H.sub.24 BrN.sub.3 O                                                 63.02% C  5.52% H   9.59% N                                    Found          63.02% C  5.47% H   9.62% N                                    ______________________________________                                    

EXAMPLE EIGHT ##STR12## 3-1-(2-Methylphenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) andalpha-bromo-2-xylene (0.63 mL) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.47 g (78%) of product, mp261-262° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O                                                 60.62% C  4.58% H   10.60% N                                   Found          60.35% C  4.45% H   10.63% N                                   ______________________________________                                    

EXAMPLE NINE ##STR13## 3-1-(4-Methylphenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) andalpha-bromo-4-xylene (0.63 mL) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.43 g (76%) of product, mp240-242° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O                                                 60.62% C  4.58% H   10.60% N                                   Found          60.46% C  4.38% H   10.60% N                                   ______________________________________                                    

EXAMPLE TEN ##STR14## 3-1-(3-Methylphenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) andalpha-bromo-3-xylene (0.64 mL) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.43 g (76%) of product, mp232-233° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O                                                 60.62% C  4.58% H   10.60% N                                   Found          60.70% C  4.63% H   10.41% N                                   ______________________________________                                    

EXAMPLE ELEVEN ##STR15## 3-1-(3-Methoxyphenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrochloride

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and3-methoxybenzyl chloride (0.68 mL) in acetonitrile (25 mL) was heatedunder reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 0.90 g (52%) ofproduct, mp 244-245° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 ClN.sub.3 O.sub.2                                           65.31% C  4.93% H   11.42% N                                   Found          65.12% C  4.61% H   11.36% N                                   ______________________________________                                    

EXAMPLE TWELVE ##STR16## 3-1-(3-Fluorophenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and3-fluorobenzyl bromide (0.58 mL) in acetonitrile (25 mL) was heatedunder reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.40 g (73%) ofproduct, mp 248-249° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrFN.sub.3 O                                                57.02% C  3.78% H   10.30% N                                   Found          56.85% C  3.48% H   10.42% N                                   ______________________________________                                    

EXAMPLE THIRTEEN ##STR17##3-11-(2-Fluorophenyl)methyl-N-4(1H-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and2-fluorobenzyl bromide (0.56 mL) in acetonitrile (25 mL) was heatedunder reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.43 g (74%) ofproduct, mp 260-261° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrFN.sub.3 O                                                57.02% C  3.78% H   10.50% N                                   Found          56.77% C  3.87% H   10.53% N                                   ______________________________________                                    

EXAMPLE FOURTEEN ##STR18## 3-1-(4-Fluorophenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and4-fluorobenzyl bromide (0.59 mL) in acetonitrile (25 mL) was heatedunder reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.38 g (73%) ofproduct, mp 259-260° C.

Analysis

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrFN.sub.3 O                                                57.02% C  3.78% H   10.50% N                                   Found          56.79% C  3.85% H   10.54% N                                   ______________________________________                                    

EXAMPLE FIFTEEN ##STR19## 3-1-(3-Nitrophenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrochloride

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and3-nitrobenzyl chloride (0.81 g) in acetonitrile (25 mL) was heated underreflux for 24 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 0.63 g (35%) of product, mp292-293° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 ClN.sub.4 O.sub.3                                           59.62% C  3.95% H   14.64% N                                   Found          59.45% C  3.91% H   14.77% N                                   ______________________________________                                    

EXAMPLE SIXTEEN ##STR20## 3-1-(2-Nitrophenyl)methyl-N-4(1H)-pyridiniminyl !-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and2-nitrobenzyl bromide (1.02 g) in acetonitrile (25 mL) was heated underreflux for 1 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.51 g (75%) of product, mp221-222° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrN.sub.4 O.sub.3                                           53.41% C  3.54% H   13.11% N                                   Found          53.34% C  3.29% H   13.09% N                                   ______________________________________                                    

EXAMPLE SEVENTEEN ##STR21## 3-1-(4-Trifluoromethylphenyl)methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and4-trifluoromethylbenzyl bromide (1.13 g) in acetonitrile (25 mL) washeated under reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.67 g (78%) ofproduct, mp 245-246° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.15 BrF.sub.3 N.sub.3 O                                          53.35% C  3.36% H  9.33% N                                    Found           53.17% C  3.39% H  9.24% N                                    ______________________________________                                    

EXAMPLE EIGHTEEN ##STR22## 3-1-(3-Trifluoromethylphenyl)methyl-N-4(1H)pyridiniminyl!-1,2-benzisoxazole hydrochloride

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g) and3-trifluoromethylbenzyl chloride (0.73 mL) in acetonitrile (25 mL) washeated under reflux for 1 hr. The mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 0.52 g (27%) ofproduct, mp 254-255° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.15 ClF.sub.3 N.sub.3 O                                          59.20% C  3.73% H  10.35% N                                   Found           59.02% C  3.64% H  10.35% N                                   ______________________________________                                    

EXAMPLE NINETEEN ##STR23## 5-Fluoro-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 5-Fluoro-3- 4-pyridinyl-amino!-1,2-benzisoxazole (0.70 g)and benzyl bromide (0.52 g) in acetonitrile (15 mL) was heated underreflux for 1.5 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.16 g (95%) of product, mp276-277° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrFN.sub.3 O                                                57.02% C  3.78% H   10.50% N                                   Found          57.04% C  3.74% H   10.42% N                                   ______________________________________                                    

EXAMPLE TWENTY ##STR24## 6-Methoxy-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 6-methoxy-3- 4-pyridinyl)amino!-1,2-benzisoxazole (0.85 g)and benzyl bromide (0.60 g) in acetonitrile (18 mL) was heated underreflux for 1.5 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected. The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.26 g (87%) of product, mp264-265° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O.sub.2                                           58.26% C  4.40% H   10.19% N                                   Found          57.89% C  4.44% H   10.11% N                                   ______________________________________                                    

EXAMPLE TWENTY-ONE ##STR25## 6-Nitro-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 6-nitro-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.80 g)and benzyl bromide (0.53 g) in acetonitrile (15 mL) was heated underreflux for 1.5 hr. The mixture was allowed to cool to room temperature,and the precipitate was collected The precipitate was washed withdiethyl ether and dried in vacuo to afford 1.23 g (92%) of product mp270-272° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrN.sub.4 O.sub.3                                           53.41% C  3.54% H   13.11% N                                   Found          53.31% C  3.32% H   13.12% N                                   ______________________________________                                    

EXAMPLE TWENTY-TWO ##STR26## 5-Fluoro-3-4-(pyridinyl)amino!-1,2-benzisoxazole A mixture of2,5-difluoro-N-4-pyridinylbenzarnide (10 g) and thionyl chloride (45 mL)was heated under reflux for 3 hr. The reaction mixture was evaporated invacuo, and the residual imidoyl chloride was used without purification.O-Trimethylsilylhydroxyl amine (10.3 g) was added rapidly to asuspension of the imidoyl chloride in tetrahydrofuran (215 mL), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas filtered, the solids were treated with saturated sodium bicarbonatesolution, and the mixture was extracted with ethyl acetate. The filtratewas treated dropwise with tetra-n-butylammonium fluoride solution (1M intetrahydrofuran, 42.7 mL). The solution was stirred at room temperaturefor 10 min., diluted with water and extracted with ethyl acetate. Thecombined organic extracts were washed with water and saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was washed with methanol. Thefiltrate was combined with the aqueous phase and basified with saturatedsodium bicarbonate solution. The layers were separated, and the aqueousphase was extracted with ethyl acetate. The combined organic extractswere washed with water and saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was washed with ethyl acetate to giveamidoxime; the total amount of amidoxime was 6.2 g (58%), used belowwithout further purification.

Potassium -t-butoxide (1.97 g) was added to a portion of the amidoxime(4.0 g) suspended in tetrahydrofuran (80 mL), and the mixture was heatedunder reflux for 12 hr. The reaction mixture was allowed to cool to roomtemperature and was diluted with water and ethyl acetate. The layerswere separated and the aqueous layer was extracted with ethyl acetate.The combined organic extracts were washed with water and saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. Recrystallization of theresidue from acetonitrile provided 2.55 g (69%) of product, mp 248-249°C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.8 FN.sub.3 O                                                   62.88% C  3.52% H   18.33% N                                   Found          62.74% C  3.51% H   18.35% N                                   ______________________________________                                    

EXAMPLE TWENTY-THREE ##STR27## 6-Chloro-3-4-pyridyl)amino!-1,2-benzisoxazole maleate

To a solution of 3-amino-6-chloro-1,2-benzisoxazole (5.0 g) inN-methylpyrrolidone (60 mL) was added 4-chloropyridine hydrochloride(9.1 g). The mixture was stirred vigorously at 130° C. for 1.5 hr. Thereaction mixture was cooled, saturated sodium bicarbonate solution andwater were added. The precipitate was collected, washed with water, airdried, and flash chromatographed on silica (7×15 cm column), elutingfirst with ethyl acetate and then with 10% methanol/ethyl acetate. Theappropriate fractions were collected and concentrated. The maleate wasformed by treatment of the residue with maleic acid in methanol.Recrystallization from ethanol gave 1.17 g (10.9%) of product, mp203(dec), after drying under high vacuum and refluxing xylenes.

Analysis:

    ______________________________________                                        Calculated for C.sub.16 H.sub.12 ClN.sub.3 O.sub.5                                           53.13% C  3.34% H   11.62% N                                   Found          53.02% C  3.14% H   11.44% N                                   ______________________________________                                    

EXAMPLE TWENTY-FOUR ##STR28## 6-Methoxy-3-4-(pyridinyl)amino!-1,2-benzisoxazole hemi-fumarate monohydrate

A mixture of 2-fluoro-4-methoxy-N-4-pyridinylbenzamide (1 1.0 g) andthionyl chloride (16 g) in dichloroethane (10 mL) was heated underreflux for 1 hr, and the reaction mixture was allowed to cool to roomtemperature. Diethyl ether was added, and the imidoyl chloride wascollected by filtration.

O-Trimethylsilylhydroxyl amine (10.6 g) was added rapidly to asuspension of the imidoyl chloride in tetrahydrofuran (220 mL), and theresulting mixture was stirred at room temperature for 20 hr. Thereaction mixture was diluted with ethyl acetate and basified withsaturated sodium bicarbonate solution. The layers were separated and theaqueous phase was extracted with ethyl acetate. The combined organicextracts were washed with water and saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. Trituration of the residue with ethyl acetate provided 9.3g of amidoxime, used below without further purification.

Potassium-t-butoxide (0.54 g) was added to a portion of the amidoxime(1.2 g) in dimethylformamide (23 mL), and the mixture was heated at 60°C. for 1 hr. The reaction mixture was allowed to cool to roomtemperature and diluted with saturated ammonium chloride solution andethyl acetate. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was chromatographed on a RAPTLC (Chromatotron™, 4 mm plate),eluting with methanol/ethyl acetate. The appropriate fractions werecollected and concentrated to provide 0.55 g (50%) of product free base.The product free base was dissolved in hot methanol and treated with anequivalent amount of fumaric acid. The precipitate was collected toafford 0.51 g of analytically pure product, mp 261-263° C.

Analysis:

    ______________________________________                                        Calculated for  56.78% C 4.77% H    18.24% N                                  C.sub.13 H.sub.13 N.sub.3 O.sub.3.0.5C.sub.4 O.sub.4 H.sub.4                  Found           56.65% C 4.74% H    12.98% N                                  ______________________________________                                    

EXAMPLE TWENTY-FIVE ##STR29## 6-Fluoro-3-4-(pyridinyl)amino!-1,2-benzisoxazole hydrochloride

A mixture of 2,4-difluoro-N-4-pyridinylbenzamide (10 g) and thionylchloride (15 g) was heated under reflux for 1 hr, and the reactionmixture was allowed to cool to room temperature. Diethyl ether wasadded, and the imidoyl chloride was collected. O-Trimethylsilylhydroxylamine (10.3 g) was added rapidly to a suspension of the imidoyl chlorideformed above in tetrahydrofuran (210 mL), and the mixture was stirred atroom temperature for 18 hr. The reaction mixture was diluted with ethylacetate and basified with saturated sodium bicarbonate solution. Thelayers were separated and the aqueous layer was extracted with ethylacetate. The combined organic extracts were washed with water andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. Trituration of theresidue with ethyl acetate provided 5.74 g) of amidoxime, used belowwithout further purification. Potassium-t-butoxide (2.3 g) was added toa portion of the amidoxime (4.7 g) suspended in tetrahydrofuran (100mL), and the mixture was heated under reflux for 0.75 hr. The reactionmixture was allowed to cool to room temperature and was diluted withwater and ethyl acetate. The layers were separated and the aqueous layerwas extracted with ethyl acetate. The combined organic extracts werewashed with water and saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. Recrystallization of the residue from ethylacetate/methanol provided 2.47 g (54%) of product free base in twocrops. The filtrates were concentrated, and the residue wasrecrystallized. Recrystallization of the residue left afterconcentration of the mother liquors from acetonitrile provided anadditional 1.12 g (26%) of product free base. A portion of the productfree base (1 g) was dissolved in hot methanol and treated withmethanolic hydrochloric acid. The precipitate was collected byfiltration to afford 0.67 g of analytically pure product, mp >300° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.9 ClFN.sub.3 O                                                 54.25% C  3.41% H   15.82% N                                   Found          54.07% C  3.64% H   15.80% N                                   ______________________________________                                    

EXAMPLE TWENTY-SIX ##STR30##7-Fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole

A mixture of 2,3-difluoro-N-4-pyridinylbenzamide (10 g) in thionylchloride (45 mL) was heated under reflux for 4 hr., the reaction mixturewas allowed to cool to room temperature and concentrated in vacuo.Dichloroethane and diethyl ether were added. The precipitated imidoylchloride (10.0 g) was collected. O-Trimethylsilylhydroxyl amine (10.3 g)was added rapidly to a suspension of the imidoyl chloride formed abovein tetrahydrofuran (210 mL), and the mixture was stirred at roomtemperature for 18 hr. 10% Hydrochloric acid (50 mL) was added, and thereaction mixture was stirred at room temperature for 1 hr. The solutionwas basified with saturated sodium bicarbonate solution and extractedwith ethyl acetate. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated.Trituration of the residue with ethyl acetate provided 5.9 g ofamidoxime, used below without further purification. Potassium-t-butoxide(1.1 g) was added to a portion of the amidoxime (2.25 g) suspended intetrahydrofuran (45 mL), and the mixture was heated under reflux for 4hr. The reaction mixture was allowed to cool to room temperature anddiluted with water and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with water and saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. Recrystallization of the residue from acetonitrileprovided 1.25 g (61%) of product, mp 234-236° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.9 FN.sub.3 O                                                   62.88% C  3.52% H   18.33% N                                   Found          62.63% C  3.35% H   18.47% N                                   ______________________________________                                    

EXAMPLE TWENTY-SEVEN ##STR31##6-Nitro-3-(4-pyridinylamino)-1,2-benzisoxazole

A mixture of 2,4-dinitro-N-4-pyridinylbenzamide (14.4 g) and phosphoruspentachloride (12.5 g) in dichloroethane (100 mL) was heated underreflux for 4 hr. The reaction mixture was allowed to cool to roomtemperature and the precipitated imidoyl chloride (13.2 g) wascollected. O-Trimethylsilylhydroxyl amine (12.1 g) was added rapidly toa suspension of the imidoyl chloride in tetrahydrofuran (200 mL), andthe mixture was stirred at room temperature for 18 hr. Subsequentaddition of water precipitated a solid (4.06 g) which was collected byfiltration. The filtrate was basified with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The layers were separated andthe aqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with water and brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated.Trituration of the residue with ethyl acetate and then hot methanol gave1.81 g of product. Combination of the two batches provided 5.86 g (39%)of amidoxime, which was used below without further purification.Potassium-t-butoxide (2.1 g) was added to a portion of the amidoxime(5.3 g) suspended in tetrahydrofuran (80 mL), and the mixture was heatedunder reflux for 2 hr. The reaction mixture was allowed to cool to roomtemperature and diluted with water and ethyl acetate. The layers wereseparated and the aqueous phase was extracted with ethyl acetate. Thecombined organic extracts were washed with water and brine, dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. Recrystallization of the residue from acetonitrileprovided 3.32 g (74%) of product, mp 296-300° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.8 N.sub.4 O.sub.3                                              62.88% C  3.52% H   18.33% N                                   Found          62.63% C  3.35% H   18.47% N                                   ______________________________________                                    

EXAMPLE TWENTY-EIGHT ##STR32## 3-1-(2-butynyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3-(4-pyridinylamino)-1,2-benzisoxazole (0.9 g) and4-bromo-2-butyne (0.86 g) in acetonitrile (25 mL) was heated underreflux for 1 hr. The reaction mixture was allowed to cool to roomtemperature and the precipitate was collected. The precipitate waswashed with diethyl ether and recrystallized from ethanol to affordproduct, mp 229-230° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.16 H.sub.14 BrN.sub.3 O                                                 55.83% C  4.10% H   12.21% N                                   Found          55.54% C  3.99% H   12.88% N                                   ______________________________________                                    

EXAMPLE TWENTY-NINE ##STR33## 3-1-(3-bromo-2-butenyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3-(4-pyridinylamino)-1,2-benzisoxazole (1 g) and2,4-dibromo-2-butene (1.51 g) in acetonitrile (25 mL) was heated underreflux for 1 hr. The reaction mixture was allowed to cool to roomtemperature, and the precipitate was collected. The precipitate waswashed with diethyl ether and dried in vacuo to afford 1.3 g (65%) ofproduct, mp 217-218° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.16 H.sub.15 Br.sub.2 N.sub.3 O                                          45.20% C  3.56% H   9.88% N                                    Found          45.36% C  3.74% H   9.94% N                                    ______________________________________                                    

EXAMPLE THIRTY ##STR34##6-Trifluoromethyl-3-(4-pyridinylamino)-1,2-benzisoxazole

A mixture of 2-fluoro4-trifluoromethyl-N-4-pyridinylbenzamide (29 g,101.8 mmol) and phosphorous pentachloride (15.9 g, 1.2 eq) indichloroethane (750 mL) was heated at reflux for one hour. The reactionmixture was allowed to cool to room temperature and diethyl ether wassubsequently added. The precipitated imidoyl chloride (25 g) wascollected by filtration. O-Trimethylsilylhydroxyl amine (19.0 g, 2.2 eq)was added rapidly to a suspension of the imidoyl chloride formed abovein tetrahydrofuran (750 mL), and the resulting mixture was stirred atroom temperature for 20 hours. Dilute hydrochloric acid was added, andthe mixture was stirred 10 minutes at room temperature. The reaction wasdiluted with ethyl acetate and carefully basified with saturated sodiumbicarbonate solution. The layers were separated and the organic phasewas dried over anhydrous magnesium sulfate, filtered and concentratedunder vacuum. The crude product (14.7 g) was triturated with ethylacetate to provide the amidoxime (12.7 g). The amidoxime was dissolvedin THF and potassium butoxide (5.2 g, 1.1 eq) was added in one portion.The reaction was stirred at room temperature for 2 hours. The reactionwas diluted with water and ethyl acetate. The organic layer wascollected and washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum. The residuewas triturated with ethyl acetate to provide the title compound (7.5 g,63%). The title compound is recrystallized from methanol, mp 249-250° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.13 H.sub.8 F.sub.3 N.sub.3 O                                            55.92% C  2.89% H   15.05% N                                   Found          55.76% C  2.73% H   15.13% N                                   ______________________________________                                    

EXAMPLE THIRTY-ONE ##STR35##5-Trifluoromethyl-3-(4-pyridinylamino)-1,2-benzisoxazole

Syn,anti 2-fluoro-5-trifluoromethylphenyl-4-pyridinylamino methanoneoxime (10.7 g, 35.8 mmol) was dissolved in THF (400 mL) and potassiumbutoxide (4.4 g, 1.1 eq) was added in one portion. The reaction wasstirred for 6 hours at room temperature under nitrogen. The reaction wasdiluted with water and ethyl acetate. The organic layer was collectedand washed with water and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under vacuum. Trituration with ethyl acetateprovided the title compound (7.0 g, 70%). The title compound isrecrystallized from methanol, mp >280° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.13 H.sub.3 F.sub.3 N.sub.3 O                                            55.92% C  2.89% H   15.05% N                                   Found          55.88% C  2.69% H   15.01% N                                   ______________________________________                                    

EXAMPLE THIRTY-TWO ##STR36## 6-Methoxy-3-4-(3-bromopyridinyl)aminol-1,2-benzisoxazole

N-Bromosuccinimide (1.8g, 1.1 eq) was added in one portion to a slurryof 6-methoxy-3- 4-pyridinylamino!-1,2-benzisoxazole (2.2 g, 9.1 mmol)and silica gel 60 (3.0 g) in carbon tetrachloride (50 mL). The mixturewas refluxed for one hour and subsequently stirred overnight at roomtemperature. The reaction was filtered and the filtrate was washed withaqueous sodium thiosulfate, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified on aPrep 500 Chromatograph (silica gel, 2% methanol/ethyl acetate) toprovide the title compound (0.97 g, 33%). The title compound isrecrystallized from methanol, mp 152-153° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.13 H.sub.10 BrN.sub.3 O.sub.2                                           48.77% C  3.15% H   13.18% N                                   Found          48.60% C  3.24% H   13.13% N                                   ______________________________________                                    

EXAMPLE THIRTY-THREE ##STR37## 6-Methoxy-3-4-(3,5-dibromopyridinyl)aminol-1,2-benzisoxazole

In a manner analogous to the procedure described in example thirty-two,the title compound (0.95 g, 26%) is prepared from 6-methoxy-3-4-pyridinylamino!-1,2-benzisoxazole (2.2 g, 9.1 mmol). The titlecompound is recrystallized from methanol, mp 180-181° C.

EXAMPLE THIRTY-FOUR ##STR38##5-Methoxy-3-(4-pyridinylamino)-1,2-benzisoxazole

In a manner analogous to the procedure described in example twenty-five,the title compound (1.2 g, 20% after recrystallization fromacetonitrile, mp 248-251° C.) is prepared from2-fluoro-5-methoxy-N-4-pyridinylbenzamide (9.39 g, 38.2 mmol). In thelast step, the intermediate is heated in N-methyl pyrrolidinone atapproximately 100° C. to provide the title compound.

EXAMPLE THIRTY-FIVE ##STR39##3-(4-Pyridinylamino)-7-trifluoromethyl-1,2-benzisoxazole

In a manner analogous to the procedure described in example thirty, thetitle compound (4.35 g, 76%, after recrystallization from acetonitrile,248-249° C. (dec)) is prepared from2-fluoro-N-(4-pyridinyl)-3-trifluoromethyl benzamide (10 g, 35.2 mmol).

EXAMPLE THIRTY-SIX ##STR40##7-Methoxy-3-(4-pyridinylamino)-1,2-benzisoxazole

In a manner analogous to the procedure described in example thirty, thetitle compound (3.0 g, 65%, after recrystallization from acetonitrile,226-227° C.) is prepared from 2-fluoro-3-methoxy-N-4-pyridinylbenzamide(25 g, 102 mmol). In the last step, the intermediate is heated inN-methyl-pyrrolidinone at approximately 100° C. to provide the titlecompound.

EXAMPLE THIRTY-SEVEN ##STR41##3-(4-pyridinylamino)-1,2-benzisoxazole-7-ol hydrobromide monohydrate

A solution of 7-methoxy-3- (4-pyridinyl)amino!-1,2-benzisoxazole (3 g,12.4 mmol) in 124 mL of a 1:1 mixture of 48% Hbr and acetic acid washeated at reflux for 24 hours. Subsequently, the mixture was allowed tocool to room temperature, and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (3.1 g, 78%), mp 270-273° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.12 BrN.sub.3 O.sub.3                                           44.19% C  3.71% H   12.88% N                                   Found          43.79% C  3.79% H   12.84% N                                   ______________________________________                                    

EXAMPLE THIRTY-EIGHT ##STR42##4-Fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole

In a manner analogous to the procedure described in example twenty-five,the title compound (2.1 g, 43%) is prepared from2,6-difluoro-N4-pyridinylbenzamide (5 g, 21.4 mmol). The title compoundis recrystallized from hot ethyl acetate, mp 160-161° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.12 H.sub.8 FN.sub.3 O                                                   62.88% C  3.52% H   18.33% N                                   Found          62.72% C  3.71% H   18.21% N                                   ______________________________________                                    

EXAMPLE THIRTY-NINE ##STR43##7-Fluoro-3-!1-phenylmethyl-N-4(1H)-pyridiniminyl!-1.2-benzisoxazolehydrobromide

A mixture of 7-fluoro-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.70 g,3.05 mmol) and benzyl bromide (0.52 g, 3.05 mmol) in acetonitrile (15mL) was heated at reflux for 1.5 hours. Subsequently, the mixture wasallowed to cool to room temperature and the precipitated product wascollected by filtration. The white solid was washed with diethyl etherand dried under vacuum to provide the title compound (1.16 g, 95%),mp >300° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 BrFN.sub.3 O                                                57.02% C  3.78% H   10.50% N                                   Found          56.78% C  3.67% H   10.73% N                                   ______________________________________                                    

EXAMPLE FORTY ##STR44## 3-1-(2-propenyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g, 4.73 mmol)and allyl bromide (0.45 mL, 1 eq) in acetonitrile (25 mL) was heated atreflux for one hour. The mixture was then allowed to cool to roomtemperature and the precipitated product was collected by filtration.The white solid was washed with diethyl ether and dried under vacuum toprovide the title compound (1.15 g, 73%), mp 250-251° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.15 H.sub.14 BrN.sub.3 O                                                 54.23% C  4.25% H   12.88% N                                   Found          54.05% C  4.21% H   12.58% N                                   ______________________________________                                    

EXAMPLE FORTY-ONE ##STR45## 3-1-(phenylmethyl)-N-4(1H)-pyridiniminyl!-6-trifluoromethyl-1,2-benzisoxazolehydrobromide

A mixture of 6-trifluoromethyl-3-(4-pyridinylamino)-1,2-benzisoxazole (1g, 3.58 mmol) and benzyl bromide (0.51 mL, 1.2 eq) in acetonitrile (25mL) was heated to reflux for one hour. The mixture was then allowed tocool to room temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (1.2 g, 74%), mp 244-245° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.15 BrF.sub.3 N.sub.3 O                                          53.35% C  3.36% H  9.33% N                                    Found           53.23% C  3.28% H  9.22% N                                    ______________________________________                                    

EXAMPLE FORTY-TWO ##STR46## 3-1-(Phenylmethyl)-N-4(1H)-pyridiniminyl!-5-trifluoromethyl-1,2-benzisoxazolehydrobromide

A mixture of 5-trifluoromethyl-3-(4-pyridinylamino)-1,2-benzisoxazole (1g, 3.58 mmol) and benzyl bromide (0.51 mL, 1.2 eq) in acetonitrile (25mL) was heated to reflux for one hour. The mixture was then allowed tocool to room temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (1.3 g, 81%) mp 274-275° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.15 BrF.sub.3 N.sub.3 O                                          53.35% C 3.36% H   9.88% N                                    Found           53.16% C 3.34% H   9.88% N                                    ______________________________________                                    

EXAMPLE FORTY-THREE ##STR47## 6-Methoxy-3-1-phenylmethyl-N-4(1H)-3-bromo-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 6-methoxy-3- 4-(3-bromopyridinyl)amino!-1,2-benzisoxazole(0.7 g, 2.2 mmol) and benzyl bromide (0.31 mL, 1.2 eq) in acetonitrile(25 mL) was heated to reflux for one hour. The mixture was then allowedto cool to room temperature and the precipitated product was collectedby filtration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (0.48 g, 45%), mp 241-242° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.17 Br.sub.2 N.sub.3 O.sub.2                                     48.91% C  3.49% H  8.66% N                                    Found           48.75% C  3.48% H  8.52% N                                    ______________________________________                                    

EXAMPLE FORTY-FOUR ##STR48## 6-Fluoro-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrochloride

A mixture of 6-fluoro-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.70 g,3.05 mmol) and benzyl bromide (0.52 g, 3.05 mmol) in acetonitrile (15mL) was heated at reflux for 1.5 hours. The mixture was allowed to coolto room temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide a white powder (1.1 g). The white powder wastreated with saturated sodium bicarbonate to make basic and the aqueoussolution was extracted with ethyl acetate. The combined organic extractswere concentrated under vacuum to provide the free base of the titlecompound (0.65 g). The free base was dissolved in hot isopropanol andtreated with a solution of HCl (g) in isopropanol. After cooling, thetitle compound was collected by filtration (0.39 g, 36%), mp 267-269° C.(dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.19 H.sub.15 ClFN.sub.3 O                                                64.14% C  4.25% H   11.81% N                                   Found          63.79% C  4.31% H   11.47% N                                   ______________________________________                                    

EXAMPLE FORTY-FIVE ##STR49## 3-1-Phenylmethyl-N-4(1H)-pyridiniminyl!-7-trifluoromethyl-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-7-trifluoromethyl-1,2-benzisoxazole(0.80 g, 2.87 mmol) and benzyl bromide (0.49 g, 2.87 mmol) inacetonitrile (15 mL) was heated at reflux for 1.5 hours. The mixture wasallowed to cool to room temperature and the precipitated product wascollected by filtration. The white solid was washed with diethyl etherand dried under vacuum to provide the title compound (0.99 g, 77%), mp275-277° C. (dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.15 BrF.sub.3 N.sub.3 O                                          53.35% C  3.36% H  9.33% N                                    Found           53.14% C  3.33% H  9.55% N                                    ______________________________________                                    

EXAMPLE FORTY-SIX ##STR50## 5-Methoxy-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 5-methoxy-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.70 g,2.9 mmol) and benzyl bromide (0.5 g, 2.9 mmol) in acetonitrile (15 mL)was heated at reflux for 1.5 hours. The mixture was allowed to cool toroom temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (1.09 g, 91%), mp 277-278° C.(dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O.sub.2                                           58.26% C  4.40% H   10.19% N                                   Found          58.11% C  4.30% H   10.32% N                                   ______________________________________                                    

EXAMPLE FORTY-SEVEN ##STR51## 4-(3-Benzod!isoxazolylimino)-1-(4H)-pyridinyl!-acetic acid methyl esterhydrobromide

A mixture of 3-(4-pyridinylamino)-1,2-benzisoxazole (0.9g, 4.3 mmol) andmethyl bromoacetate (0.44 mL, 1. 1 eq) in acetonitrile (25 mL) washeated at reflux for one hour. The mixture was then allowed to cool toroom temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (1 g, 70%), mp 235-236° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.15 H.sub.14 BrN.sub.3 O.sub.3                                           49.47% C  3.87% H   11.54% N                                   Found          49.48% C  3.90% H   11.67% N                                   ______________________________________                                    

EXAMPLE FORTY-EIGHT ##STR52## 7-Methoxy-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromide

A mixture of 7-methoxy-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.70 g,2.9 mmol) and benzyl bromide (0.5 g, 2.9 mmol) in acetonitrile (15 mL)was heated at reflux for 1.5 hours. The mixture was then allowed to coolto room temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether and driedunder vacuum to provide the title compound (0.99 g, 83%), mp 253-254° C.(dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.20 H.sub.18 BrN.sub.3 O.sub.2 :                                          58.26% C  4.40% H  10.19% N                                   Found:          57.99% C  4.56% H  10.26% N                                   ______________________________________                                    

EXAMPLE FORTY-NINE ##STR53## 4-Fluoro-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydrobromidehemihydrate

A mixture of 4-fluoro-3- (4-pyridinyl)amino!-1,2-benzisoxazole (0.8 g,3.5 mmol) and benzyl bromide (0.42 g, 1 eq) in acetonitrile (50 mL) washeated at reflux for one hour. The mixture was then allowed to cool toroom temperature and the precipitated product was collected byfiltration. The white solid was washed with diethyl ether to provide thetitle compound (0.8g, 57%). The title compound is recrystallized frommethanol/isopropanol, mp 200-201° C.

Analysis:

    ______________________________________                                        Calculated for  55.75% C  3.95% H  10.27% N                                   C.sub.19 H.sub.15 BrFN.sub.3 O.0.5H.sub.2 O:                                  Found:          56.11% C  4.03% H  10.51% N                                   ______________________________________                                    

EXAMPLE FIFTY ##STR54## 6-Fluoro-3-1-methyl-N-4(1H)-pyridiniminyl!-12-benzisoxazole hydroiodide

A mixture of 6-fluoro-3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.43 g,6.24 mmol) and methyl iodide (0.89 g, 6.24 mmol) in acetonitrile (30 mL)was heated at reflux for 1.5 hours. The mixture was then allowed to coolto room temperature and the precipitated product was collected byfiltration. The slightly yellow solid was washed with diethyl ether anddried under vacuum to provide the title compound (1.93 g, 83%), mp272-275° C. (dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.13 H.sub.11 FIN.sub.3 O:                                                 42.07% C  2.99% H  11.32% N                                   Found:          42.07% C  2.92% H  11.31% N                                   ______________________________________                                    

EXAMPLE FIFTY-ONE ##STR55## 6-Methoxy-3-1-methyl-N-4(1H)-pyridiniminyl!-1,2-benzisoxazole hydroiodide

A mixture of 6-methoxy-3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.1 g,4.56 mmol) and methyl iodide (0.65 g, 4.56 mmol) in acetonitrile (20 mL)was heated at reflux for 1.5 hours. The mixture was then allowed to cooland the precipitated product was collected by filtration. The slightlyyellow solid was washed with diethyl ether and dried under vacuum toprovide the title compound (1.5 g, 86%), mp 262-264° C. (dec).

Analysis:

    ______________________________________                                        Calculated for C.sub.14 H.sub.14 IN.sub.3 O.sub.2 :                                           43.88% C  3.68% H  10.97% N                                   Found:          43.77% C  3.58% H  10.96% N                                   ______________________________________                                    

EXAMPLE FIFTY-TWO ##STR56## 3-1-(Trans-3-phenyl-2-propenyl)-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3- (4-pyridinyl)amino!-1,2-benzisoxazole (1.0 g, 4.73 mmol)and cinnamyl bromide (0.93 g, 1 eq) in acetonitrile (25 mL) was heatedat reflux for one hour. The mixture was then allowed to cool and theprecipitated product was collected by filtration. The white solid waswashed with diethyl ether and dried under vacuum to provide the titlecompound (1.8 g, 93%), mp 243-244° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.21 H.sub.18 BrN.sub.3 O:                                                 61.78% C  4.44% H  10.29% N                                   Found:          61.67 C   4.27% H  10.34% N                                   ______________________________________                                    

EXAMPLE FIFTY-THREE ##STR57## 3- 1-2-(1,3-dioxalane)ethyl!-N-4(1H)-pyridiniminyl!-1,2-benzisoxazolehydrobromide

A mixture of 3-(4-pyridinylamino)-1,2-benzisoxazole (1.2 g, 5.7 mmol)and 2-(2-bromoethyl)-1,3-dioxolane (0.73 mL, 1.1 eq) in acetonitrile (25mL) was heated to reflux for one hour. The mixture was then allowed tocool and the precipitate product was collected by filtration. The whitesolid was washed with diethyl ether and dried under vacuum to providethe title compound (0.95 g, 42%). The title compound was recrystallizedfrom ethanol, mp 220-22 1° C.

Analysis:

    ______________________________________                                        Calculated for C.sub.17 H.sub.18 BrN.sub.3 O.sub.3 :                                          52.05% C  4.63% H  10.71% N                                   Found:          51.86 C   4.51% H  10.52% N                                   ______________________________________                                    

EXAMPLE FIFTY-FOUR ##STR58## 7-Chloro-3-4-(pyridinyl)amino!-1,2-benzisothiazole

4-Chloropyridine hydrochloride (2.2 eq) is added to3-amino-7-chloro-1,2-benzisothiazole (1 eq) in N-methylpyrolidone. Themixture is stirred at 130° C. for 1.5 hours. The resulting mixture iscooled, and then saturated sodium bicarbonate solution and water areadded. The title compound is extracted into ethyl acetate, the combinedorganic extracts are washed with water, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum. The residueis purified by column chromatography on silica gel to provide the titlecompound.

EXAMPLE FIFTY-FIVE ##STR59## 7-Chloro-3-1-phenylmethyl-N-4(1H)-pyridiniminyl!-1,2-benzisothiazole hydrobromide

7-Chloro-3- 4-(pyridinyl)amino!-1,2-benzisothiazole (1 eq) and benzylbromide (1 eq) are combined in acetonitrile and heated at reflux for 1.5hours. The mixture is then allowed to cool and the precipitated productis collected by filtration and dried under vacuum to provide the titlecompound. ##STR60##

We claim:
 1. A compound of the formula: wherein Q is hydrogen, halogen, loweralkyl or nitro: X is oxygen; Z is loweralkyl, loweralkoxy, hydroxyl, fluoro, bromo, iodo, nitro or trifluoromethyl; the optical isomers, or pharmaceutically acceptable salts thereof.
 2. A compound according to claim 1 which is 5-fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole.
 3. A compound according to claim 1 which is 6-methoxy-3-(4-PYRIDINYLAMINO)-1,2-benzisoxazole.
 4. A compound according to claim 1 which is 6-fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole.
 5. A compound according to claim 1 which is 7-fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole.
 6. A compound according to claim 1 which is 6-nitro-3-(4-pyridinylamino)-1,2-benzisoxazole.
 7. A compound according to claim 1 which is 6-trifluoromethyl-3-(4-pyridinylamino)-1,2-benzisoxazole.
 8. A compound according to claim 1 which is 5-trifluoromethyl-3-(4-PYRIDINYLAMINO)-1,2-benzisoxazole.
 9. A compound according to claim 1 which is 6-methoxy-3- 4-(3-bromopyridinyl)amino!-1,2-benzisoxazole.
 10. A compound according to claim 1 which is 5-methoxy-3-(4-pyridinylamino)-1,2-benzisoxazole.
 11. A compound according to claim 1 which is 3-(4-pyridinylamino)-7-trifluoromethyl-1,2-benzisoxazole.
 12. A compound according to claim 1 which is 7-methoxy-3-(4-pyridinylamino)-1,2-benzisoxazole.
 13. A compound according to claim 1 which is 3-(4-pyridinylamino)-1,2-benzisoxazole-7-ol.
 14. A compound according to claim 1 which is 4-fluoro-3-(4-pyridinylamino)-1,2-benzisoxazole.
 15. A compound which is 6-methoxy-3- 4-(3,5-dibromopyridinyl)amino!-1,2-benzisoxazole.
 16. A memory dysfunction relieving composition comprising an adjuvant and as the active ingredient, a memory dysfunction relieving effective amount of a compound of claim
 1. 17. A method of relieving memory dysfunction in mammals comprising administering to a mammal requiring memory dysfunction relief, a memory dysfunction relieving effective amount of a compound of claim
 1. 